Mechanism of inhibition by ethanol of NMDA and AMPA receptor channel functions in cultured rat cortical neurons

Abstract

The effect and mode of action of ethanol on N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors of rat cortical neurons in primary culture were compared by means of the patch-clamp technique. The maxima of the concentration-response curves for both NMDA and AMPA were markedly depressed by ethanol without an apparent shift of the curves to the right. Ethanol inhibited the effects of NMDA and AMPA concentration-dependently and equally well. Excitatory amino acid (EAA) currents were depressed to the largest extent when ethanol was continuously superfused during and between agonist applications; a smaller inhibitory effect was observed when ethanol was intermittently superfused during agonist applications only. There was no inhibition by ethanol, when its superfusion was between two agonist applications. According to expectations, the analysis of the ratios of plateau to peak currents failed to suggest a use-dependent blockade by ethanol. In addition, comparison of the voltage-current curves of NMDA and AMPA in the absence and presence of ethanol indicated a voltage-independent effect and no change in the reversal potential of the two agonists. Finally, the measurement of activation and deactivation time constants for the ethanol-induced inhibition of NMDA and AMPA responses confirms the failure of ethanol to cause an open-channel block. In conclusion, these findings as a whole indicate that ethanol inhibits NMDA and AMPA currents by a noncompetitive mechanism. The mode of action appears to be similar for both NMDA and AMPA; under the conditions of the present study, a selective interference with structural motifs of the NMDA receptor is unlikely.

Synaptic targets: Chronic alcohol actions

“…Acute ethanol also inhibits the function of AMPARs (Akinshola et al, 2001; Akinshola et al, 2003; Dildy-Mayfield and Harris, 1992; Moykkynen et al, 2003; Nieber et al, 1998; Wirkner et al, 2000) although with lower potency than NMDARs (Frye and Fincher, 2000; Lovinger, 1995; Lovinger et al, 1989). EtOH slightly alters AMPAR-mediated synaptic responses [the amplitude or time course of EPSCs] at most synapses due to increased receptor desensitization (Ariwodola et al, 2003; Lovinger et al, 1990; Moykkynen et al, 2003; Moykkynen et al, 2009), but see (Mameli et al, 2005; Nie et al, 1993; Roberto et al, 2004b; Zhu et al, 2007).…”

Targeting glutamate uptake to treat alcohol use disorders

“…Moreover, the effects of ethanol consumption on NMDA- and mGlu-R as well as Homer (a glutamatergic receptor scaffolding protein) subunit expression in the extended amygdala and Acb core are also influenced by the length of ethanol-withdrawal (Obara et al, 2009 ). Intracellularly, ethanol inhibits, non-competitively, the NMDAR-mediated calcium influx in the cortex, Acb, amygdala, hippocampus, and VTA (Nie et al, 1994 ; Wirkner et al, 2000 ; Roberto et al, 2004 ; Stobbs et al, 2004 ; Zhu et al, 2007 ). Additionally, ethanol's effects on NMDA receptor activity are followed by phosphorylation and internalization of NR2 subunits (Suvarna et al, 2005 ).…”

Neuropeptide modulation of central amygdala neuroplasticity is a key mediator of alcohol dependence

“…Low concentrations (5–50 mM) of alcohol also inhibit AMPAR function (Akinshola et al, 2001; Dildy-Mayfield and Harris, 1992, Moykkynen et al, 2003; Wirkner et al, 2000). Our lab has shown that acute alcohol (5–66 mM) decreases excitatory post-synaptic potentials (EPSPs) and currents (EPSCs) in the CeA, and that these effects are mediated by both NMDAR and non-NMDAR mechanisms (Roberto et al, 2004b).…”